All references, including patents and patent applications, are hereby incorporated by reference in their entireties.
EP4 receptor agonists are reported to be useful in lowering intraocular pressure and to have application in treating glaucoma. Prasanna, G. et al., Exp. Eye Res., 2009, 89 (5), 608-17; Luu, K. et al., J. Pharmacol. Exp. Ther. 2009, 331(2), 627-635; Saeki, T. et al, Invest. Ophthalmol. Vis. Sci., 2009, 50 (5) 2201-2208.
EP4 receptor agonists are also reported to induce bone remodeling and to have use in the treatment of osteoporosis. Iwaniec, U. et al., Osteoporosis International, 2007, 18 (3), 351-362; Aguirre, J. et al., J. Bone and Min. Res., 2007, 22(6), 877-888; Yoshida, K. et al., Proc. Natl. Acad. Sci. USA, 2002, 99 (7), 4580-4585. Hayashi, K. et al., J. Bone Joint Surg. Br., 2005, 87-B (8), 1150-6.
Applicants have discovered that various 1,5-disubstituted 3,3-difluoropyrrolidin-2-ones (α,α-difluorolactams, or difluorolactams) have potent EP4 receptor agonist activity. A published method of fluorine incorporation into the lactam scaffold possesses inherent inefficiencies for manufacturing large-scale quantities of a key difluorolactam intermediate and subsequent intermediates and target compounds; namely, a protection step requiring either impractically-large volumes of solvent and reagent for large scale production or involving smaller volumes but with repetitive manipulation, and a cumbersome two-step electrophilic fluorination process. Allen, N. E. et al., Tetrahedron, 1989, 45, 1905-1928; Konas, D. W. and Coward, J. K., Organic Letters, 1999, 1(13), 2105-2107; Martinez-Montero, S. et al., Bioorganic and Medicinal Chemistry, 2012, 20(23), 6885-6893; and Qian, X. et al., WO 2009023193. Further intermediates and methods described herein for synthesis of difluorolactam compounds provide efficiencies comprising the incorporation chiral carbon atom centers with high stereochemical purity and facilitation of efficient attachment of functionalized organic chains.